Field of the Invention
The present invention relates to a novel compound and a crystalline form thereof that are metabolized in vivo to form a compound having utility as a neprilysin-inhibitor. The invention also relates to pharmaceutical compositions comprising compound, processes for preparing this compound, and methods of using compound to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.
State of the Art
Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn2+ metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriuresis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.
NEP inhibitors, such as thiorphan, candoxatril, and candoxatrilat, have been studied as potential therapeutics. Compounds that inhibit both NEP and angiotensin-I converting enzyme (ACE) are also known, and include omapatrilat, gempatrilat, and sampatrilat. Referred to as vasopeptidase inhibitors, this latter class of compounds is described in Robl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677.
Numerous NEP inhibitors are described in U.S. Patent Application Publication No. 2013/0109639 to Hughes, et al. One such compound is (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-4-(oxalylamino)pentanoic acid, which has the structure:
This compound exhibits potent NEP inhibition activity (pKi≧9). However, this compound has also been found to have very low oral bioavailability in preclinical species, making it unsuitable or undesirable for oral administration.
One method for increasing the oral bioavailability of a compound is to form a prodrug of the compound. When orally administered, a prodrug should have acceptable oral absorption and be cleaved in vivo to generate the active compound. For NEP inhibitors, it may be preferable that any such prodrug be cleaved rapidly (e.g., within the first hour following oral administration) and completely so that an initial bolus of active compound is available to trigger a cyclic guanosine monophosphate (cGMP) response. It may also be desirable if the prodrug itself has NEP inhibition activity so that the prodrug can contribute to pharmacologic activity before it is cleaved. Moreover, any such prodrug should be chemically stable when stored for a prolonged period of time.
Thus, there exists a need for a prodrug of (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-4-(oxalylamino)pentanoic acid that has acceptable oral absorption and which is rapidly cleaved in vivo to generate the active compound. The prodrug may also have some level of NEP inhibitory activity. This invention is directed to that need.
Additionally, to effectively use a NEP inhibitor compound as a therapeutic agent, it would be desirable to have a solid-state form that can be readily manufactured and that has acceptable chemical and physical stability. For example, it would be highly desirable to have a physical form that is thermally stable at reasonably high temperature, thereby facilitating processing and storage of the material. Crystalline solids are generally preferred over amorphous forms, for enhancing purity and stability of the manufactured product. However, the formation of crystalline forms of organic compounds is highly unpredictable. No reliable methods exist for predicting which, if any, form of an organic compound will be crystalline. Moreover, no methods exist for predicting which, if any, crystalline form will have the physically properties desired for use as pharmaceutical agents. Accordingly, a need exists for a stable, crystalline form which has a reasonably high melting point.